Control of the Circulation Control of the circulation depends on a variety of mechanisms that are directly related to the specific functions that the circulation performs.

Functions of the Circulation Function of the circulation Delivery of oxygen, glucose, amino acids, fatty acids. Removal of carbon dioxide and hydrogen ions. Maintenance of ion concentraions. Transport of hormones.

Variations in Blood Flow Large metabolic requirements:  Heart, brain, active muscle Need to process lots of blood  Kidney, liver, lungs Special cases:  Skin – for cooling in hot weather.

Methods of Regulation Vasodilator: Lack of oxygen produces lactic acid, adenosine (degradation of ATP) which directly affect vascular tone. Oxygen demand: Lack of oxygen prevents SMC from sustaining contraction. (But smc can remain contracted with extremely low oxygen). Need for other nutrients: e.g. vitamin B, as in beriberi.

Hyperemia Active Hyperemia: As a result of exercise.  Can increase blood up to 20-fold. Reactive Hyperemia: As a result of ischemia.  Used as a test for coronary stenosis.

Local Response to Pressure Metabolic: Increased pressure increases flow, leading to increased oxygen, tending to constrict the vessels. Mechanical: Stretch receptors in smooth muscle cause vascular constriction. Might lead to positive feedback.

Ability to compensate for pressure changes Arterial Pressure Blood Flow Chronic Acute 250 mm Hg 10 L

Special Mechanisms of Control Kidney (tubuloglomerular feedback): fluid composition in the distal tubule is detected by the macular densa. Excess fluid causes reduced flow rate. Brain: Oxygen, CO 2 and Hydrogen Ion play a dominant role.

Control of Large Vessel Tone EDRF (NO): Produced by endothelial cells. An EC response to shear stress. Also produced in response to acetylcholine, bradykinin, ATP. Potent vasodilator. Leads to post-stenotic dilitation. Has other purposes: Neurotransmitter, platelet inhibitor, inhibits cell proliferation

NO and Super Oxide NO is produced by NOS Requires L-arginine as substrate. Without L-arginine, NOS produces Super- Oxide, which can do major damage. It is thought that lack of L-arginine during reperfusion may be a major cause of reperfusion injury.

NO and Bacteria NO is a primitive immune response. Does not so much kill bacteria as maintain them in stasis so that they will not proliferate and grow. Produced during wound healing as a first line of defense.

NO and Viagra Viagra stimulates the production of NO.

Vasoconstrictors Angiotensin: 1 micro gram can cause 50 mm Hg increase in pressure. Acts on all arterioles Vasopression: Made in hypothalamus – released to pituitary from which it is distributed to the body. Highly potent. Controls flow in renal tubules

Vasoconstrictors (contd) Endothelin Effective in nanogram quantitites. Probably major mechanism for preventing bleeding from large arterioles (up to 0.5 mm). Constricts the umbilical artery of a neonate. Especially effective on coronary, renal, mesenteric and cerebral arteries.

Vasodilators Bradykinin: Causes arteriole dilation and increased capillary permeability. Kallerikin -> Kallikrein* (acts on) alpha 2 -globulin (releases) kallidin -> bradykinin (inactivated by) carboxypeptidase (or) converting enzyme Regulates flow to skin, salivary glands, gastrointestinal glands.

Vasodilators (continued) Serotonin (5-hydroxytryptamine or 5HT):  Found in platelets (potentiator of platelet activation).  Neurotransmitter.  May be vasoconstrictor or vasodilator.  Role in circulation control not fully understood.

Vasodilators (continued) Histamine:  Released by damaged tissue.  Vasodilator and increases capillary porosity.  May induce edema.  Major part of allergic reactions. Prostaglandins:  Most are vasodilators, some are vasoconstrictors.  Pattern of function not yet understood.

Other Ions Calcium: Vasoconstrictor (smc contraction) Potassium: Vasodilator (inhibit smc contraction) Magnesium: Vasodilator (inhibit smc contraction) Sodium: Mild dilatation caused by change in osmolality. Increased osmolality causes dilitation. Acetate and Citrate: Mild vasodilators. Increased CO 2 /pH: Vasodilation

CARDIAC OUTPUT

Cardiac Output, Venous Return and their Regulation Cardiac output is controlled to maintain the proper amount of flow to tissues and to prevent undue stress on the heart.

Cardiac Output Generally proportional to body surface area. Cardiac Index (CI): Approximately 3 liters/min/m 2 of body surface area. CI varies with age, peaking at around 8 years.

Frank-Starling Law What goes into the heart comes out. Increased heart volume stretches muscles and causes stronger contraction. Stretch increases heart rate as well. Direct effect on sino-atrial node Bainbridge reflex (through the brain)

Cardiac Output Depends on venous return, which, in turn, depends on the rate of flow to the tissues. Rate of flow to tissues depends on tissue needs (i.e. it depends on Total Peripheral Resistance). Therefore, cardiac output is proportional to the energy requirements of the tissues.

Limit of Cardiac Output Normal CO – 5 L/min Plateau – 13 L/min Hypereffective heart plateau – 20 L/min Hypoeffective heart plateau – 5 L/min

Hypereffective Heart Effected by: 1.Nervous excitation. 2.Cardiac Hypertrophy  Exercise – Marathon runners may get 30 to 40 L/min  Aortic Valve Stenosis

Hypoeffective Heart Valvular disease Increased output pressure Congential heart disease Myocarditis Cardiac anoxia Toxicity

Autonomic Nervous System Causes increased cardiac output when vessels become dilated (dinitrophenol). Causes venous constriction during exercise.

Disease States Lowering Total Peripheral Resistance Beriberi: insufficient thiamine – tissues starve because they cannot use nutrients. AV fistula: e.g. for dialysis. Hyperthyroidism: Reduced resistance caused by increased metabolism Anemia (lack of RBCs): effects viscosity and transport of O 2 to the tissues.

Disease States Lowering Cardiac Output Heart attack, valvular disease, myocarditis, cardiac tamponade, shock. Shock: Nutritional deficiency of tissues. Decreased venous return caused by:  Reduced blood volume  Venous dilitation (increased circulatory volume)  Venous obstruction

Changes in Intrapleural Pressure Generally shift the cardiac output curve in proportion to pressure change (breathing, Valsalva maneuver). Cardiac Tamponade (filling of pericardial sac with fluid) lowers rate of change of CO with right atrial pressure Heart Pericardial Sac Rt. Atrial Pressure CO tamponade 15 L/min

Determinants of Venous Return Mean systemic filling pressure Right Atrial Pressure Resistance to Flow Pressure change is slight. Thus, small increase in RA Pressure causes dramatic reduction in venous return. (mean systemic filling pressure).

Normal Venous Return Curve 5 L/min VR (CO) Rt. Atrial Pressure (mm Hg) 0 -4 Mean systemic filling pressure ~ 7 mm Hg Plateau: collapse of large veins ( => increased resistance) Venous return with heart and lung removed.

Filling Pressure Mean Circulatory: The pressure within the circulatory system when all flow is stopped (e.g. by stopping the heart). Mean Systemic: Pressure when flow is stopped by clamping large veins. The two are close numerically.

Compensation for Increased Blood Volume 1.Increased CO increases capillary pressure, sending more fluid to tissues. 2.Vein volume increases 3.Pooling of blood in the liver and spleen 4.Increased peripheral resistance reduces cardiac output.

Effects of Sympathetic Stimulation Increases contractility of the heart. Decreases volume by contracting the veins. Increases filling pressure Increases resistance

Effects of Sympathetic Inhibition Shifts CO to the right Shifts venous return down and to the left - Reduced CO 5 L/min VR (CO) Rt. Atrial Pressure (mm Hg) 0 -4 Venous return with heart and lung removed.

Effects of AV Fistula 1.Decreased VR resistance. 2.Slight increased CO because of reduced peripheral resistance. After restoration of pressure (sympathetic) 1.Further CO increase. 2.Increased filling pressure. 3.Decreased kidney output (leads to higher fluid volume and more increase in CO). 4.Cardiac hypertrophy (caused by increased workload).

Measurement of CO Electromagnetic/ultrasonic (transit time) flow meter. Oxygen Fick method: CO = (Rate of O2 absorbed by lungs) [O2] la - [O2] rv Indicator dilution method: Inject cold saline (or dye) into RA, measure temperature (or concentration) in aorta.